VCV000002782.12 - ClinVar

NM_000158.4(GBE1):c.1571G>A (p.Arg524Gln)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000158.4(GBE1):c.1571G>A (p.Arg524Gln)

Variation ID: 2782 Accession: VCV000002782.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p12.2 3: 81577972 (GRCh38) [ NCBI UCSC ] 3: 81627123 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Jun 17, 2024	Jan 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000158.4:c.1571G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000149.4:p.Arg524Gln	missense
NC_000003.12:g.81577972C>T
NC_000003.11:g.81627123C>T
NG_011810.1:g.188829G>A
	Q04446:p.Arg524Gln

... more HGVS ... less HGVS

Protein change

R524Q

Other names

NM_000158.4(GBE1):c.1571G>A

Canonical SPDI

NC_000003.12:81577971:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD) 0.00003

Links

ClinGen: CA115753 UniProtKB: Q04446#VAR_022434 OMIM: 607839.0007 dbSNP: rs80338673 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GBE1		-	-	GRCh38 GRCh37	1008	1024

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Glycogen storage disease IV, combined hepatic and myopathic	Pathogenic (1)	no assertion criteria provided	Sep 28, 2004	RCV000002915.11
Glycogen storage disease, type IV	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 29, 2024	RCV000020162.8
Adult polyglucosan body neuropathy	Pathogenic (1)	no assertion criteria provided	Sep 28, 2004	RCV000150107.10
Glycogen storage disease IV, classic hepatic Glycogen storage disease, type IV	Pathogenic (1)	criteria provided, single submitter	Jan 2, 2024	RCV001043400.6

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 02, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Glycogen storage disease, type IV Glycogen storage disease IV, classic hepatic Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001207144.3 First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024	Publications: PubMed (5) PubMed: 10545044‚ 10762170‚ 12874416‚ 15452297‚ 20479904 Comment: This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 524 of the GBE1 protein (p.Arg524Gln). … (more) This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 524 of the GBE1 protein (p.Arg524Gln). This variant is present in population databases (rs80338673, gnomAD 0.007%). This missense change has been observed in individual(s) with glycogen storage disease IV (PMID: 10545044, 10762170, 12874416, 15452297, 20479904). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2782). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GBE1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Jan 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Glycogen storage disease, type IV (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV002097090.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022	Comment: The p.Arg524Gln variant in GBE1 has been reported in 6 individuals with GBE1-related disorders (PMID: 10762170, 15452297, 20479904, 33332610, 33726816, Pan 2017) and has been … (more) The p.Arg524Gln variant in GBE1 has been reported in 6 individuals with GBE1-related disorders (PMID: 10762170, 15452297, 20479904, 33332610, 33726816, Pan 2017) and has been identified in 0.004% (1/23800) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs80338673). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of the 6 affected individuals, 1 was a compound heterozygotes that carried a reported likely pathogenic variants in trans, 1 was a homozygote, and 1 was a compound heterozygote that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the p.Arg524Gln variant is pathogenic (VariationID: 2789, 208584; PMID: 15452297, 33726816). This variant has also been reported in ClinVar (Variation ID#: 2782) and has been interpreted as pathogenic by Invitae, OMIM, and GeneReviews. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for GBE1-related disorders. ACMG/AMP Criteria applied: PP3, PM3_strong, PM2_supporting (Richards 2015). (less)
Pathogenic (Jul 31, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Glycogen storage disease, type IV Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004030058.1 First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023	Publications: PubMed (7) PubMed: 31127727‚ 15452297‚ 33332610‚ 33726816‚ 20479904‚ 12874416‚ 10762170 Comment: Variant summary: GBE1 c.1571G>A (p.Arg524Gln) results in a conservative amino acid change to a highly conserved residue (HGMD) located in the Glycosyl hydrolase, family 13, … (more) Variant summary: GBE1 c.1571G>A (p.Arg524Gln) results in a conservative amino acid change to a highly conserved residue (HGMD) located in the Glycosyl hydrolase, family 13, catalytic domain (IPR006047) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 243710 control chromosomes (gnomAD). c.1571G>A has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type IV (Bruno_2004, Ziemssen_2000, Ban_2009, Derks_2021, Stranneheim_2021, Sindern_2003, Westra_2019), and some were reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15452297, 10762170, 20479904, 33332610, 33726816, 12874416, 31127727). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jan 29, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease, type IV Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004198686.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Sep 28, 2004)	no assertion criteria provided Method: literature only	GLYCOGEN STORAGE DISEASE IV, COMBINED HEPATIC AND MYOPATHIC Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023073.7 First in ClinVar: Apr 04, 2013 Last updated: Dec 31, 2022	Publications: PubMed (3) PubMed: 10545044‚ 15452297‚ 10762170 Comment on evidence: Glycogen Storage Disease IV In a 16-month-old infant with a combination of hepatic and muscular features of glycogen storage disease IV (GSD4; 232500), Bruno et … (more) Glycogen Storage Disease IV In a 16-month-old infant with a combination of hepatic and muscular features of glycogen storage disease IV (GSD4; 232500), Bruno et al. (1999) identified compound heterozygosity for a G-to-A transition in the GBE1 gene, resulting in an arg524-to-gln (R524Q) substitution, while the other allele was not expressed. The patient was the only child of healthy, unrelated parents. At birth he presented with severe hypotonia, flexion contractures of hips, knees, ankles, elbows, and wrists, and neck pterygium. At age 5 months, he was admitted to hospital for surgical correction of arthrogryposis. At that time, muscle hypotonia, stunted growth, hepatosplenomegaly, and liver dysfunction were noted. Laboratory investigations showed increased levels of liver enzymes, while serum creatine kinase remained normal. Electromyography showed a myopathic pattern, with pseudomyotonic discharges. The status of the patient at 22 months of age suggested that the liver dysfunction and the myopathy were static, that respiratory function was not affected, and that there was no abnormality of the heart or of mental development. In a follow-up study of the patient reported by Bruno et al. (1999), Bruno et al. (2004) identified a second GBE1 mutation on the other allele (607839.0014). Adult Polyglucosan Body Neuropathy In a non-Ashkenazi patient with adult polyglucosan body neuropathy (APBN; 263570), Ziemssen et al. (2000) identified compound heterozygosity for the arg524-to-gln mutation and an R515H mutation (607839.0019) in the GBE1 gene. (less)
Pathogenic (Sep 28, 2004)	no assertion criteria provided Method: literature only	ADULT POLYGLUCOSAN BODY NEUROPATHY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000196931.5 First in ClinVar: Jan 29, 2015 Last updated: Dec 31, 2022	Publications: PubMed (3) PubMed: 10545044‚ 15452297‚ 10762170 Comment on evidence: Glycogen Storage Disease IV In a 16-month-old infant with a combination of hepatic and muscular features of glycogen storage disease IV (GSD4; 232500), Bruno et … (more) Glycogen Storage Disease IV In a 16-month-old infant with a combination of hepatic and muscular features of glycogen storage disease IV (GSD4; 232500), Bruno et al. (1999) identified compound heterozygosity for a G-to-A transition in the GBE1 gene, resulting in an arg524-to-gln (R524Q) substitution, while the other allele was not expressed. The patient was the only child of healthy, unrelated parents. At birth he presented with severe hypotonia, flexion contractures of hips, knees, ankles, elbows, and wrists, and neck pterygium. At age 5 months, he was admitted to hospital for surgical correction of arthrogryposis. At that time, muscle hypotonia, stunted growth, hepatosplenomegaly, and liver dysfunction were noted. Laboratory investigations showed increased levels of liver enzymes, while serum creatine kinase remained normal. Electromyography showed a myopathic pattern, with pseudomyotonic discharges. The status of the patient at 22 months of age suggested that the liver dysfunction and the myopathy were static, that respiratory function was not affected, and that there was no abnormality of the heart or of mental development. In a follow-up study of the patient reported by Bruno et al. (1999), Bruno et al. (2004) identified a second GBE1 mutation on the other allele (607839.0014). Adult Polyglucosan Body Neuropathy In a non-Ashkenazi patient with adult polyglucosan body neuropathy (APBN; 263570), Ziemssen et al. (2000) identified compound heterozygosity for the arg524-to-gln mutation and an R515H mutation (607839.0019) in the GBE1 gene. (less)
not provided (-)	no classification provided Method: literature only	Glycogen storage disease, type IV Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000040489.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (4) PubMed: 10545044‚ 10762170‚ 15452297‚ 20301758 BookShelf: NBK5300 BookShelf: NBK5300

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 524 of the GBE1 protein (p.Arg524Gln). This variant is present in population databases (rs80338673, gnomAD 0.007%). This missense change has been observed in individual(s) with glycogen storage disease IV (PMID: 10545044, 10762170, 12874416, 15452297, 20479904). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2782). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GBE1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.Arg524Gln variant in GBE1 has been reported in 6 individuals with GBE1-related disorders (PMID: 10762170, 15452297, 20479904, 33332610, 33726816, Pan 2017) and has been identified in 0.004% (1/23800) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs80338673). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of the 6 affected individuals, 1 was a compound heterozygotes that carried a reported likely pathogenic variants in trans, 1 was a homozygote, and 1 was a compound heterozygote that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the p.Arg524Gln variant is pathogenic (VariationID: 2789, 208584; PMID: 15452297, 33726816). This variant has also been reported in ClinVar (Variation ID#: 2782) and has been interpreted as pathogenic by Invitae, OMIM, and GeneReviews. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for GBE1-related disorders. ACMG/AMP Criteria applied: PP3, PM3_strong, PM2_supporting (Richards 2015).

Comment:

Variant summary: GBE1 c.1571G>A (p.Arg524Gln) results in a conservative amino acid change to a highly conserved residue (HGMD) located in the Glycosyl hydrolase, family 13, catalytic domain (IPR006047) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 243710 control chromosomes (gnomAD). c.1571G>A has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type IV (Bruno_2004, Ziemssen_2000, Ban_2009, Derks_2021, Stranneheim_2021, Sindern_2003, Westra_2019), and some were reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15452297, 10762170, 20479904, 33332610, 33726816, 12874416, 31127727). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients.	Stranneheim H	Genome medicine	2021	PMID: 33726816
The potential of dietary treatment in patients with glycogen storage disease type IV.	Derks TGJ	Journal of inherited metabolic disease	2021	PMID: 33332610
GBE1 Adult Polyglucosan Body Disease.	Adam MP	-	2020	PMID: 20301758
Panel-Based Exome Sequencing for Neuromuscular Disorders as a Diagnostic Service.	Westra D	Journal of neuromuscular diseases	2019	PMID: 31127727
Living Donor Liver Transplantation in a Korean Child with Glycogen Storage Disease Type IV and a GBE1 Mutation.	Ban HR	Gut and liver	2009	PMID: 20479904
Clinical and genetic heterogeneity of branching enzyme deficiency (glycogenosis type IV).	Bruno C	Neurology	2004	PMID: 15452297
Adult polyglucosan body disease: a postmortem correlation study.	Sindern E	Neurology	2003	PMID: 12874416
Novel missense mutations in the glycogen-branching enzyme gene in adult polyglucosan body disease.	Ziemssen F	Annals of neurology	2000	PMID: 10762170
A novel missense mutation in the glycogen branching enzyme gene in a child with myopathy and hepatopathy.	Bruno C	Neuromuscular disorders : NMD	1999	PMID: 10545044

Text-mined citations for rs80338673 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000158.4(GBE1):c.1571G>A (p.Arg524Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80338673 ...